EP3970700A1 - A solid oral pharmaceutical formulation comprising eltrombopag olamine - Google Patents

A solid oral pharmaceutical formulation comprising eltrombopag olamine Download PDF

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Publication number
EP3970700A1
EP3970700A1 EP21197089.2A EP21197089A EP3970700A1 EP 3970700 A1 EP3970700 A1 EP 3970700A1 EP 21197089 A EP21197089 A EP 21197089A EP 3970700 A1 EP3970700 A1 EP 3970700A1
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EP
European Patent Office
Prior art keywords
solid oral
oral pharmaceutical
pharmaceutical formulation
formulation according
eltrombopag olamine
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP21197089.2A
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German (de)
French (fr)
Inventor
Fatih Sunel
Gulcin TOK
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
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Sanovel Ilac Sanayi ve Ticaret AS
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Publication of EP3970700A1 publication Critical patent/EP3970700A1/en
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4152—1,2-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. antipyrine, phenylbutazone, sulfinpyrazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds

Definitions

  • the present invention relates to a solid oral pharmaceutical formulation comprising the particle size d(0.9) of the eltrombopag olamine is less than 10 ⁇ m.
  • the formulation eliminates problems of the active agent and provide additional advantages to the relevant prior art.
  • THPO Thrombopoietin
  • MGDF megakaryocyte growth and development factor
  • thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts.
  • Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches for activating the thrombopoietin receptor were sought.
  • thrombopoietin receptor agonists Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for other thrombocytopenic conditions.
  • Eltrombopag olamine is a peptide-like, small molecular weight agonist of the thrombopoietin receptor. This agent is given by mouth and result in significant increases in platelet counts in normal persons as well as patients with idiopathic thrombocytopenic purpura (ITP).
  • ITP idiopathic thrombocytopenic purpura
  • Eltrombopag olamine is a small molecular weight peptide-like molecule that binds to the transmembrane domain of the thrombopoietin receptor and causes its activation and the proliferation and differentiation of megakaryocytes, with a resultant increase in synthesis and release of platelets.
  • eltrombopag olamine was shown to raise the platelet count in patients with idiopathic thrombocytopenic purpura (ITP), aplastic anemia and cirrhosis due to chronic hepatitis C during interferon therapy.
  • ITP idiopathic thrombocytopenic purpura
  • Eltrombopag olamine was approved for use in the United States in 2008 for the treatment of ITP and its indications have subsequently been expanded to other thrombocytopenic conditions.
  • EP1889838B1 is the molecule patent of eltrombopag olamine.
  • Another application EP3041511A2 discloses pharmaceutical compounds of eltrombopag olamine in the form of tablets and the methods for their preparation.
  • Eltrombopag olamine presents the formulator with unique concerns when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form, suitably a tablet, suitably a capsule, with a desirable pharmacokinetic profile. Some of the concerns is that slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, and the tendency of the compound to under-go a Maillard reaction when contacted with excipients that contain reducing sugars. In other words, eltrombopag olamine is very sensitive for some excipients and environmental effects.
  • EP3615007 discloses a pharmaceutical tablet composition comprising eltrombopag olamine and one or more reducing sugars, a production process therefore, a pharmaceutical tablet composition comprising eltrombopag olamine and one or more reducing sugars obtainable by the production process.
  • WO03/098992 discloses an eltrombopag tablet composition comprising 8.45 mg eltrombopag olamine, furthermore 112 mg microcrystallinecellulose, 70 mg lactose, 8 mg sodium starch glycolate and 2 mg magnesium stearate.
  • micronized eltrombopag olamine provided great advantages in the dissolution profile and hence bioavailability.
  • a unique formulation has been created with compatible excipients and micronized eltromopag olamine.
  • the main object of the present invention is to provides a solid oral pharmaceutical formulation comprising eltrombopag olamine having desired dissolution profile, stability (chemical stability or towards dehydration and/or storage stability) for the treatment of conditions leading to thrombocytopenia.
  • the particle size seems to play an active role in increasing the solubility of the active substance, eltrombopag olamine, and providing an appropriate bioavailability.
  • particle size refers to the cumulative volume size distribution tested by any conventionally recognised method, such as a laser diffraction method.
  • d (0.9) means the size at which 90% by volume of the particles are finer.
  • the particle size distribution of D (0.9) overcome the problems encountered in the prior art by increasing the solubility of eltrombopag olamine, resulting in enhanced bioavailability of the solid oral formulation.
  • a solid oral pharmaceutical formulation comprises eltrombopag olamine and at least one pharmaceutically acceptable excipient, wherein the particle size d (0.9) of the eltrombopag olamine is less than 10 ⁇ m.
  • the particle size helps to ensure the desired dissolution profile.
  • the particle size d (0.9) of eltrombopag olamine is preferably between 9 ⁇ m and 1 ⁇ m or between 8 ⁇ m and 2 ⁇ m, between 7 ⁇ m and 3 ⁇ m, between 6 ⁇ m and 4 ⁇ m.
  • the amount of eltrombopag olamine is between 5.0% and 30.0% by weight in the total formulation.
  • the amount of eltrombopag olamine is between 7.0% and 28.0% by weight in the total formulation.
  • the formulation comprises at least one pharmaceutical acceptable excipient which are selected from binders, diluents, disintegrants, glidants, lubricants or mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer, polycarbophil, polyethylene oxide, polymethacrylates, stearic acid, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  • polyvinylpyrrolidone povidone
  • natural gums agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer,
  • the amount of binders is between 0.1% and 5.0% in the total formulation.
  • the binder is polyvinylpyrrolidone. Using polyvinylpyrrolidone helps to provide homogeneous formulation, even when used in small amounts.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, sucrose, sorbitol, xylitol, inositol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • the amount of diluents is between 30.0% and 85.0% in the total formulation.
  • the diluents is microcrystalline cellulose or mannitol or mixtures thereof.
  • the use of mannitol or microcrystalline cellulose contributes to maintaining the stability in the formulation, particularly by balancing the moisture-sensitive active ingredient eltrombopag olamine with its non-hygroscopic property.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, polyacryline potassium, poloxamer, sodium alginate, sodium glycine carbonate, sodium dodecyl sulfate or mixtures thereof.
  • the amount of disintegrants is between 2.0% and 20.0% in the total formulation.
  • the disintegrant is croscarmellose sodium.
  • Suitable glidants are selected from the group comprising talc, colloidal silica, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • the amount of glidants is between 0.1% and 3.0% in the total formulation.
  • the glidant is colloidal silicon dioxide.
  • Suitable lubricants are selected from group comprising sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, zinc stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, sodium benzoate or mixtures thereof.
  • the amount of lubricants is between 1.0% and 5.0% in the total formulation.
  • the lubricant is sodium stearyl fumarate.
  • the formulation comprises eltrombopag olamine, microcrystalline cellulose, mannitol, polyvinylpyrrolidone (povidon k-30), croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate.
  • the solid oral pharmaceutical formulation is in the form of tablets, capsules, strips, pastilles, sachets.
  • the solid oral pharmaceutical formulation is in the form of capsule.
  • the solid oral pharmaceutical formulation is in the form of tablet, preferably film-coated tablet, which may vary in shape and be, e.g., round, oval, oblong, cylindrical, caplet shaped or any other suitable shape, preferably it is round or caplet shaped.
  • process of preparing the composition is wet granulation, dry granulation, hot melt extrusion, direct compression, spray drying or mixtures thereof.
  • the solid oral pharmaceutical formulation is obtained by using a wet granulation method.
  • the solid oral pharmaceutical formulation is for use in preventing or treating conditions leading to thrombocytopenia.
  • Example 1 The capsule or tablet formulation comprising Eltrombopag Olamine
  • Example 2 The capsule or tablet formulation comprising Eltrombopag Olamine
  • Formulation 1 Formulation 2
  • Formulation 3 Eltrombopag Olamine 15.95 mg 63.8 mg 95.7 mg Microcrystalline cellulose 130.94 mg 180.37 mg 98.85 mg Mannitol 14.875 mg 59.5 mg 89.25 mg Polyvinylpyrrolidone (Povidon K-30) 1.6 mg 6.4 mg 9.6 mg Croscarmellose Sodium 8.335 mg 33.33 mg 50 mg Colloidal silicon dioxide 1.75 mg 3.5 mg 3.5 mg Sodium stearyl fumarate 4.05 mg 8.1 mg 8.1 mg Coating (For tablet) 5.325 mg 10.65 mg 10.65 mg Total weight 182.825 365.65 365.65

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The present invention relates to a solid oral pharmaceutical formulation comprising the particle size d(0.9) of the eltrombopag olamine is less than 10 µm. The formulation eliminates problems of the active agent and provide additional advantages to the relevant prior art.

Description

    Field of the Invention
  • The present invention relates to a solid oral pharmaceutical formulation comprising the particle size d(0.9) of the eltrombopag olamine is less than 10 µm. The formulation eliminates problems of the active agent and provide additional advantages to the relevant prior art.
    • Background of the Invention
  • Thrombopoietin (THPO), also known as megakaryocyte growth and development factor (MGDF), is a protein that in humans is encoded by the THPO gene.
  • The thrombopoietin receptor agonists mimic the action of thrombopoietin on its receptor and stimulate the activation, proliferation and maturation of megakaryocytes, resulting in an increase in circulating platelet counts. Thrombopoietin itself acts in this manner, but when recombinant thrombopoietins were used clinically, they were found to cause rebound thrombocytopenia, probably due to induction of anti-thrombopoietin antibodies. For this reason, direct administration of thrombopoietin was abandoned as an approach to treating thrombocytopenia and other approaches for activating the thrombopoietin receptor were sought.
  • Two thrombopoietin receptor agonists were subsequently developed and are now in clinical use for chronic idiopathic thrombocytopenic purpura (ITP) and for other thrombocytopenic conditions.
  • Eltrombopag olamine is a peptide-like, small molecular weight agonist of the thrombopoietin receptor. This agent is given by mouth and result in significant increases in platelet counts in normal persons as well as patients with idiopathic thrombocytopenic purpura (ITP).
  • Eltrombopag olamine is a small molecular weight peptide-like molecule that binds to the transmembrane domain of the thrombopoietin receptor and causes its activation and the proliferation and differentiation of megakaryocytes, with a resultant increase in synthesis and release of platelets. In multiple clinical trials, eltrombopag olamine was shown to raise the platelet count in patients with idiopathic thrombocytopenic purpura (ITP), aplastic anemia and cirrhosis due to chronic hepatitis C during interferon therapy. Eltrombopag olamine was approved for use in the United States in 2008 for the treatment of ITP and its indications have subsequently been expanded to other thrombocytopenic conditions.
    Figure imgb0001
  • In the state of art, the application EP1889838B1 is the molecule patent of eltrombopag olamine. Another application EP3041511A2 discloses pharmaceutical compounds of eltrombopag olamine in the form of tablets and the methods for their preparation.
  • Eltrombopag olamine presents the formulator with unique concerns when attempting to formulate this compound into a suitable solid oral pharmaceutical dosage form, suitably a tablet, suitably a capsule, with a desirable pharmacokinetic profile. Some of the concerns is that slow dissolution of the compound from solid dosage forms, the tendency of the compound to form insoluble metal complexes when contacted with excipients that contain a coordinating metal, and the tendency of the compound to under-go a Maillard reaction when contacted with excipients that contain reducing sugars. In other words, eltrombopag olamine is very sensitive for some excipients and environmental effects.
  • EP3615007 (A1 ) discloses a pharmaceutical tablet composition comprising eltrombopag olamine and one or more reducing sugars, a production process therefore, a pharmaceutical tablet composition comprising eltrombopag olamine and one or more reducing sugars obtainable by the production process.
  • WO03/098992 (A2 ) discloses an eltrombopag tablet composition comprising 8.45 mg eltrombopag olamine, furthermore 112 mg microcrystallinecellulose, 70 mg lactose, 8 mg sodium starch glycolate and 2 mg magnesium stearate.
  • In this sense, there is still a need for an eltrombopag olamine formulation in the solid form which eliminates the above described problem of eltrombopag olamine and which enhances the dissolution profile and bioavailability of the final pharmaceutical formulation.
  • In the present invention, it is found that the use of micronized eltrombopag olamine provided great advantages in the dissolution profile and hence bioavailability. Considering the above described disadvantages of the active ingredient, a unique formulation has been created with compatible excipients and micronized eltromopag olamine.
    • Detailed Description of the Invention
  • The main object of the present invention is to provides a solid oral pharmaceutical formulation comprising eltrombopag olamine having desired dissolution profile, stability (chemical stability or towards dehydration and/or storage stability) for the treatment of conditions leading to thrombocytopenia.
  • According to an embodiment of the present invention, in the solid oral pharmaceutical formulation comprising the eltrombopag olamine, the particle size seems to play an active role in increasing the solubility of the active substance, eltrombopag olamine, and providing an appropriate bioavailability.
  • The term "particle size" refers to the cumulative volume size distribution tested by any conventionally recognised method, such as a laser diffraction method. The term d (0.9) means the size at which 90% by volume of the particles are finer.
  • Particularly, the particle size distribution of D (0.9) overcome the problems encountered in the prior art by increasing the solubility of eltrombopag olamine, resulting in enhanced bioavailability of the solid oral formulation.
  • According to an embodiment of the present invention, a solid oral pharmaceutical formulation comprises eltrombopag olamine and at least one pharmaceutically acceptable excipient, wherein the particle size d (0.9) of the eltrombopag olamine is less than 10 µm. The particle size helps to ensure the desired dissolution profile.
  • According to an embodiment of the present invention, the particle size d (0.9) of eltrombopag olamine is preferably between 9 µm and 1 µm or between 8 µm and 2 µm, between 7 µm and 3 µm, between 6 µm and 4 µm.
  • According to an embodiment of the present invention, the amount of eltrombopag olamine is between 5.0% and 30.0% by weight in the total formulation.
  • According to an embodiment of the present invention, the amount of eltrombopag olamine is between 7.0% and 28.0% by weight in the total formulation.
  • According to one embodiment of the present invention, the formulation comprises at least one pharmaceutical acceptable excipient which are selected from binders, diluents, disintegrants, glidants, lubricants or mixtures thereof.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone (povidone), natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer, polycarbophil, polyethylene oxide, polymethacrylates, stearic acid, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  • According to one embodiment of the present invention, the amount of binders is between 0.1% and 5.0% in the total formulation.
  • According to one embodiment of the present invention, the binder is polyvinylpyrrolidone. Using polyvinylpyrrolidone helps to provide homogeneous formulation, even when used in small amounts.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, sucrose, sorbitol, xylitol, inositol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • According to one embodiment of the present invention, the amount of diluents is between 30.0% and 85.0% in the total formulation.
  • According to one embodiment of the present invention, the diluents is microcrystalline cellulose or mannitol or mixtures thereof. In the current state of art, the use of mannitol or microcrystalline cellulose contributes to maintaining the stability in the formulation, particularly by balancing the moisture-sensitive active ingredient eltrombopag olamine with its non-hygroscopic property.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, sodium starch glycolate, alginic acid, alginates, ion-exchange resins, sodium carboxymethyl cellulose, carboxymethyl cellulose, calcium carboxymethyl cellulose, docusate sodium, low substituted hydroxypropyl cellulose, polyacryline potassium, poloxamer, sodium alginate, sodium glycine carbonate, sodium dodecyl sulfate or mixtures thereof.
  • According to one embodiment of the present invention, the amount of disintegrants is between 2.0% and 20.0% in the total formulation.
  • According to one embodiment of the present invention, the disintegrant is croscarmellose sodium.
  • Suitable glidants are selected from the group comprising talc, colloidal silica, magnesium silicate, magnesium oxide, starch or mixtures thereof.
  • According to one embodiment of the present invention, the amount of glidants is between 0.1% and 3.0% in the total formulation.
  • According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.
  • Suitable lubricants are selected from group comprising sodium stearyl fumarate, magnesium stearate, stearic acid, calcium stearate, zinc stearate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, sodium benzoate or mixtures thereof.
  • According to one embodiment of the present invention, the amount of lubricants is between 1.0% and 5.0% in the total formulation.
  • According to one embodiment of the present invention, the lubricant is sodium stearyl fumarate.
  • According to one embodiment of the present invention, the formulation comprises eltrombopag olamine, microcrystalline cellulose, mannitol, polyvinylpyrrolidone (povidon k-30), croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate.
  • According to one embodiment of the present invention, the solid oral pharmaceutical formulation is in the form of tablets, capsules, strips, pastilles, sachets.
  • According to one embodiment of the present invention, the solid oral pharmaceutical formulation is in the form of capsule.
  • According to one embodiment of the present invention, the solid oral pharmaceutical formulation is in the form of tablet, preferably film-coated tablet, which may vary in shape and be, e.g., round, oval, oblong, cylindrical, caplet shaped or any other suitable shape, preferably it is round or caplet shaped.
  • According to one embodiment of the present invention, process of preparing the composition is wet granulation, dry granulation, hot melt extrusion, direct compression, spray drying or mixtures thereof.
  • According to one embodiment of the present invention, the solid oral pharmaceutical formulation is obtained by using a wet granulation method.
  • According to one embodiment of the present invention, the solid oral pharmaceutical formulation is for use in preventing or treating conditions leading to thrombocytopenia.
    • Example 1: The capsule or tablet formulation comprising Eltrombopag Olamine
  • Ingredients % by weight
    Eltrombopag Olamine 5.0- 30
    Microcrystalline cellulose 25.0 - 75.0
    Mannitol 5.0 - 27.0
    Polyvinylpyrrolidone (Povidon K-30) 0.1 - 5.0
    Croscarmellose Sodium 2.0 - 20.0
    Colloidal silicon dioxide 0.1 - 3.0
    Sodium stearyl fumarate 1.0 - 5.0
    TOTAL 100
    • Example 2: The capsule or tablet formulation comprising Eltrombopag Olamine
  • Formulation 1 Formulation 2 Formulation 3
    Eltrombopag Olamine 15.95 mg 63.8 mg 95.7 mg
    Microcrystalline cellulose 130.94 mg 180.37 mg 98.85 mg
    Mannitol 14.875 mg 59.5 mg 89.25 mg
    Polyvinylpyrrolidone (Povidon K-30) 1.6 mg 6.4 mg 9.6 mg
    Croscarmellose Sodium 8.335 mg 33.33 mg 50 mg
    Colloidal silicon dioxide 1.75 mg 3.5 mg 3.5 mg
    Sodium stearyl fumarate 4.05 mg 8.1 mg 8.1 mg
    Coating (For tablet) 5.325 mg 10.65 mg 10.65 mg
    Total weight 182.825 365.65 365.65
  • Process for example 1 or 2;
    1. a) Mixing eltrombopag olamine, microcrystalline cellulose, mannitol, polyvinylpyrrolidone,
    2. b) Granulating the mixture with pure water in a high-shear wet-granulator,
    3. c) Sieving the mixture,
    4. d) Drying the mixture in the fluid bed dryer,
    5. e) Sieving the mixture and obtained homogenous powder,
    6. f) Then, mixing microcrystalline cellulose, croscarmellose sodium and colloidal silicon dioxide and adding to the mixture from step (e),
    7. g) Adding sodium stearyl fumarate and mixing,
    8. h) For capsule; Filling the powder mixture into the hard gelatin capsule or
  • For tablet; Compressing to form of tablets and coating tablets with film coating.

Claims (15)

  1. A solid oral pharmaceutical formulation comprising eltrombopag olamine and at least one pharmaceutically acceptable excipient, wherein the particle size (0.9) of the eltrombopag olamine is less than 10 µm.
  2. The solid oral pharmaceutical formulation according to claim 1, wherein the particle size d (0.9) of eltrombopag olamine is preferably between 9 µm and 1 µm or between 8 µm and 2 µm, between 7 µm and 3 µm, between 6 µm and 4 µm.
  3. The solid oral pharmaceutical formulation according to claim 1, wherein the amount of eltrombopag olamine is between 5.0% and 30.0% by weight in the total formulation.
  4. The solid oral pharmaceutical formulation according to claim 1, wherein the formulation comprising at least one pharmaceutical acceptable excipient which are selected from binders, diluents, disintegrants, glidants, lubricants or mixtures thereof.
  5. The solid oral pharmaceutical formulation according to claim 4, wherein binders are selected from the group comprising polyvinylpyrrolidone (povidone), natural gums, agar, alginates, carbomers, carboxymethylcellulose sodium, cellulose acetate phthalate, copovidone, starch, starch mucilage, dextrates, ethylcellulose, glyceryl behenate, guar gum, methylcellulose, poloxamer, polycarbophil, polyethylene oxide, polymethacrylates, stearic acid, cetostearyl alcohol, polyoxyethilene-alkyl ethers, pullulan or mixtures thereof.
  6. The solid oral pharmaceutical formulation according to claim 5, wherein the amount of binders is between 0.1% and 5.0% in the total formulation.
  7. The solid oral pharmaceutical formulation according to claim 5, wherein the binder is polyvinylpyrrolidone.
  8. The solid oral pharmaceutical formulation according to claim 4, wherein diluents are selected from the group comprising microcrystalline cellulose, mannitol, spray-dried mannitol, sucrose, sorbitol, xylitol, inositol, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  9. The solid oral pharmaceutical formulation according to claim 8, wherein the amount of diluents is between 30.0% and 85.0% in the total formulation.
  10. The solid oral pharmaceutical formulation according to claim 8, wherein the diluent is microcrystalline cellulose or mannitol or mixtures thereof.
  11. The solid oral pharmaceutical formulation according to claim 4, wherein the formulation comprising eltrombopag olamine, microcrystalline cellulose, mannitol, polyvinylpyrrolidone (povidon k-30), croscarmellose sodium, colloidal silicon dioxide, sodium stearyl fumarate.
  12. The solid oral pharmaceutical formulation according to claim 1, wherein the solid oral pharmaceutical formulation is in the form of tablets, capsules, strips, pastilles, sachets.
  13. The solid oral pharmaceutical formulation according to claim 12, wherein the solid oral pharmaceutical formulation is in the form of capsule.
  14. The solid oral pharmaceutical formulation according to claim 12, wherein the solid oral pharmaceutical formulation is in the form of tablet.
  15. The solid oral pharmaceutical formulation according to claim 1, wherein the formulation is obtained by using a wet granulation method.
EP21197089.2A 2020-09-16 2021-09-16 A solid oral pharmaceutical formulation comprising eltrombopag olamine Withdrawn EP3970700A1 (en)

Applications Claiming Priority (1)

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TR2020/14694A TR202014694A1 (en) 2020-09-16 2020-09-16 ELTROMBOPAG A SOLID ORAL PHARMACEUTICAL FORMULATION CONTAINING OLAMINE

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CN115919789A (en) * 2022-12-08 2023-04-07 山东新时代药业有限公司 A kind of Eltrombopag ethanolamine tablet and preparation method thereof
CN117281780B (en) * 2023-11-24 2024-02-02 山东则正医药技术有限公司 Eltrombopag ethanolamine dry suspension and preparation method thereof

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WO2003098992A2 (en) 2002-05-22 2003-12-04 Smithkline Beecham Corporation 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
WO2008136843A1 (en) * 2007-05-03 2008-11-13 Smithkline Beecham Corporation Novel pharmaceutical composition
EP1889838B1 (en) 2000-05-25 2009-10-14 SmithKline Beecham Corporation Thrombopoietin mimetics
EP3041511A2 (en) 2013-09-02 2016-07-13 Hetero Research Foundation Compositions of eltrombopag
WO2018078644A1 (en) * 2016-10-24 2018-05-03 Hetero Labs Limited Orally disintegrating tablets of eltrombopag
EP3615007A1 (en) 2017-04-26 2020-03-04 Alfred E. Tiefenbacher (GmbH & Co. KG) Pharmaceutical tablet composition comprising eltrombopag olamine

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WO2020055364A2 (en) * 2018-08-02 2020-03-19 Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi A pharmaceutical composition comprising eltrombopag olamine

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Publication number Priority date Publication date Assignee Title
EP1889838B1 (en) 2000-05-25 2009-10-14 SmithKline Beecham Corporation Thrombopoietin mimetics
WO2003098992A2 (en) 2002-05-22 2003-12-04 Smithkline Beecham Corporation 3'-[(2z)-[1-(3,4-dimethylphenyl)-1,5-dihydro-3-methyl-5-oxo-4h-pyrazol-4-ylidene]hydrazino]-2'-hydroxy-[1,1'-biphenyl]-3-carboxylic acid bis-(monoethanolamine)
WO2008136843A1 (en) * 2007-05-03 2008-11-13 Smithkline Beecham Corporation Novel pharmaceutical composition
EP3041511A2 (en) 2013-09-02 2016-07-13 Hetero Research Foundation Compositions of eltrombopag
WO2018078644A1 (en) * 2016-10-24 2018-05-03 Hetero Labs Limited Orally disintegrating tablets of eltrombopag
EP3615007A1 (en) 2017-04-26 2020-03-04 Alfred E. Tiefenbacher (GmbH & Co. KG) Pharmaceutical tablet composition comprising eltrombopag olamine

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